Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, variable release, oral:
Simcor:
500/20: Niacin 500 mg [extended release] and simvastatin 20 mg [immediate release] [DSC]
500/40: Niacin 500 mg [extended release] and simvastatin 40 mg [immediate release] [DSC]
750/20: Niacin 750 mg [extended release] and simvastatin 20 mg [immediate release] [DSC]
1000/20: Niacin 1000 mg [extended release] and simvastatin 20 mg [immediate release] [DSC]
1000/40: Niacin 1000 mg [extended release] and simvastatin 40 mg [immediate release] [DSC]
Pharmacology
Mechanism of Action
Niacin is a component of two coenzymes which is necessary for tissue respiration, lipid metabolism, and glycogenolysis; inhibits the synthesis of very low density lipoproteins.
Simvastatin is a derivative of lovastatin that acts by competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis. In addition to the ability of HMG-CoA reductase inhibitors to decrease levels of high-sensitivity C-reactive protein (hsCRP), they also possess pleiotropic properties including improved endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of platelet aggregation, and anticoagulant effects (de Denus, 2002; Ray, 2005).
Use: Labeled Indications
Primary hypercholesterolemia/mixed dyslipidemia/hypertriglyceridemia: Reduce total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides (TG), or increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia, mixed dyslipidemia, or hypertriglyceridemia in combination with standard cholesterol-lowering diet when simvastatin or niacin monotherapy is inadequate.
Note: Niacin is no longer considered a primary or secondary agent for dyslipidemias. Although niacin consistently affects surrogate markers, especially LDL-C, it has not been shown to reduce cardiovascular disease outcomes beyond that achieved with statin use and may be associated with harm (ACC 2016; Garg 2017; Wierzbicki 2014). In two large clinical trials, the addition of niacin to patients receiving simvastatin did not reduce cardiovascular morbidity or mortality (Boden 2011; Landray 2014). May consider use in patients with very high triglyceride levels (>500 mg/dL) or in dyslipidemia for patients who do not achieve the desired response or have intolerance to a statin or other alternative therapy (Boden 2014; Flink 2015).
Guideline recommendations: Simvastatin: Primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) to reduce the risk of ASCVD in select adult patients (ACC/AHA [Stone 2013]; ADA 2017a; NLA [Jacobson 2015]; USPSTF 2016). Refer to respective guideline for specific recommendations.
Contraindications
Hypersensitivity to niacin, simvastatin, or any component of the formulation; active liver disease; unexplained persistent elevations of transaminases; active peptic ulcer disease; arterial bleeding; pregnancy or women who may become pregnant; breastfeeding; concomitant use of strong CYP3A4 inhibitors (eg, clarithromycin, erythromycin, protease inhibitors [including boceprevir and telaprevir], itraconazole, ketoconazole, nefazodone, posaconazole, voriconazole, telithromycin, cobicistat-containing products), amiodarone, cyclosporine, danazol, diltiazem, dronedarone, gemfibrozil, verapamil
Dosage and Administration
Dosing: Adult
Primary hypercholesterolemia/mixed dyslipidemia/hypertriglyceridemia: Oral: Note: Niacin is no longer recommended, except in specific clinical situations (eg, high triglyceride levels [>500 mg/dL], if not able to achieve desired response, or intolerance to other therapies) (ACC 2016; Boden 2014; Garg 2017; Landray 2014; Wierzbicki 2014).
Initial dose: Note: Not for use as initial therapy of dyslipidemias. Doses should be individualized according to the baseline LDL-cholesterol levels, the recommended goal of therapy, and the patient's response.
Patients naïve to niacin ER therapy or currently on immediate-release niacin: Niacin ER 500 mg/simvastatin 20 mg once daily at bedtime; increase dose every 4 weeks as needed in increments of not more than 500 mg of niacin.
Patients currently on simvastatin (20 to 40 mg daily): Niacin ER 500 mg/simvastatin 40 mg once daily at bedtime; increase dose every 4 weeks as needed in increments of not more than 500 mg of niacin.
Maintenance dose: Niacin ER 1,000 to 2,000 mg/simvastatin 20 to 40 mg once daily (maximum daily dose: niacin ER 2,000 mg/simvastatin 40 mg).
Note: If therapy is interrupted for >7 days, reinstitution of therapy should begin with the lowest dose followed by retitration as tolerated. May be substituted for equivalent dose of niacin extended-release, however, manufacturer does not recommend direct substitution with immediate-release preparations.
Dosage adjustment with concomitant medications:
Amiodarone, amlodipine, or ranolazine: Maximum: Niacin ER 1,000 mg/simvastatin 20 mg per day
Lomitapide: Reduce simvastatin dose by 50% when initiating lomitapide. Simvastatin dose should not exceed 20 mg/day (or 40 mg daily for those who previously tolerated simvastatin 80 mg daily for ≥1 year without evidence of muscle toxicity).
Dosing: Geriatric
Refer to adult dosing.
Dosing: Adjustment for Toxicity
Hepatic toxicity: Discontinue use if hepatic transaminase levels rise, particularly to 3 x ULN and are persistent, or if they are associated with symptoms of nausea, fever, and/or malaise.
Severe muscle symptoms or fatigue: Promptly discontinue use; evaluate CPK, creatinine, and urinalysis for myoglobinuria (AHA/ASA [Stone 2013]).
Mild to moderate muscle symptoms: Discontinue use until symptoms can be evaluated; evaluate patient for conditions that may increase the risk for muscle symptoms (eg, hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases). Upon resolution, resume the original or lower dose of simvastatin. If muscle symptoms recur, discontinue simvastatin use. After muscle symptom resolution, may then use a low dose of a different statin; gradually increase if tolerated. In the absence of continued statin use, if muscle symptoms or elevated CPK continues after 2 months, consider other causes of muscle symptoms. If determined to be due to another condition aside from statin use, may resume statin therapy at the original dose (AHA/ASA [Stone 2013]).
Administration
Administer tablets whole; do not break, crush or chew. Administer with a low-fat snack at bedtime. To attenuate flushing symptoms, may premedicate with aspirin 30 minutes before dose; avoid ingestion of alcohol, hot or spicy foods/liquids concurrently with niacin.
Dietary Considerations
Administer with a low-fat snack; avoid alcohol, hot drinks, and spicy foods around the time of administration. Red yeast rice contains variable amounts of several compounds that are structurally similar to HMG-CoA reductase inhibitors, primarily monacolin K (or mevinolin) which is structurally identical to lovastatin; concurrent use of red yeast rice with HMG-CoA reductase inhibitors may increase the incidence of adverse and toxic effects (Lapi 2008; Smith 2003).
Storage
Store at controlled room temperature of 20°C to 25°C (68°F to 77°F).
Drug Interactions
Acipimox: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy
Alcohol (Ethyl): May enhance the adverse/toxic effect of Niacin. Consider therapy modification
Amiodarone: May increase the serum concentration of Simvastatin. Management: Consider using a non-interacting statin (pravastatin) in patients on amiodarone. If combined, limit the adult simvastatin dose to 20 mg daily and monitor for evidence of simvastatin toxicities (eg, myalgia, liver function test elevations, rhabdomyolysis). Consider therapy modification
AmLODIPine: May increase the serum concentration of Simvastatin. Management: Avoid the concurrent use of amlodipine with simvastatin when possible. If used together, avoid doses of simvastatin greater than 20 mg/day (for adults). Consider therapy modification
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Asunaprevir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy
Azithromycin (Systemic): May enhance the myopathic (rhabdomyolysis) effect of Simvastatin. Monitor therapy
Bezafibrate: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Bezafibrate may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). More specifically, bezafibrate may increase the serum concentration of fluvastatin Management: Monitor patients closely for myopathy with concomitant use of bezafibrate and HMG-CoA reductase inhibitors. Concomitant use is contraindicated in patients predisposed to myopathy and alternative therapy should be considered. Consider therapy modification
Bile Acid Sequestrants: May decrease the absorption of Niacin. Consider therapy modification
Bosentan: May decrease the serum concentration of Simvastatin. Monitor therapy
Cilostazol: May increase the serum concentration of Simvastatin. Monitor therapy
Ciprofibrate: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Management: Avoid the use of HMG-CoA reductase inhibitors and ciprofibrate if possible. If concomitant therapy is considered, benefits should be carefully weighed against the risks, and patients should be monitored closely for signs/symptoms of muscle toxicity. Consider therapy modification
Clarithromycin: May increase the serum concentration of Simvastatin. Avoid combination
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Colchicine: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Colchicine may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Consider therapy modification
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
CycloSPORINE (Systemic): May increase the serum concentration of Simvastatin. Avoid combination
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Simvastatin. Avoid combination
Cyproterone: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Avoid use of statins metabolized by CYP3A4 (eg, simvastatin) and consider avoiding fluvastatin as well in patients receiving high dose cyproterone (300 mg/day). Consider use of pravastatin, rosuvastatin, or pitavastatin if statin therapy is needed. Consider therapy modification
Dabigatran Etexilate: Simvastatin may enhance the anticoagulant effect of Dabigatran Etexilate. Monitor therapy
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Daclatasvir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy
Danazol: May increase the serum concentration of Simvastatin. Avoid combination
DAPTOmycin: Simvastatin may enhance the adverse/toxic effect of DAPTOmycin. Avoid combination
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
DilTIAZem: Simvastatin may increase the serum concentration of DilTIAZem. DilTIAZem may increase the serum concentration of Simvastatin. Management: Avoid concurrent use of diltiazem with simvastatin when possible. If used together, limit adult doses to simvastatin 10 mg/day and diltiazem 240 mg/day; avoid Simcor (simvastatin/niacin) because fixed simvastatin doses exceed the maximum. Consider therapy modification
Dronedarone: May increase the serum concentration of Simvastatin. Management: Limit simvastatin to a max of 10 mg/day (in adults). Increase monitoring for signs of simvastatin toxicity (e.g., myositis, rhabdomyolysis). Consider therapy modification
Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Efavirenz: May decrease the serum concentration of Simvastatin. Monitor therapy
Elbasvir: May increase the serum concentration of Simvastatin. Monitor therapy
Eltrombopag: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Monitor therapy
Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Erythromycin (Systemic): May increase the serum concentration of Simvastatin. Avoid combination
Eslicarbazepine: May decrease the serum concentration of Simvastatin. Monitor therapy
Etravirine: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). This applies to atorvastatin, lovastatin and simvastatin. Monitor therapy
Fenofibrate and Derivatives: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy
Fluconazole: May increase the serum concentration of Simvastatin. Monitor therapy
Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Fosphenytoin: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Consider therapy modification
Fostamatinib: May increase the serum concentration of Simvastatin. Monitor therapy
Fusidic Acid (Systemic): May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Specifically, the risk for muscle toxicities, including rhabdomyolysis may be significantly increased. Management: Avoid concurrent use whenever possible. Use is listed as contraindicated in product characteristic summaries in several countries, although UK labeling suggests that use could be considered under exceptional circumstances and with close supervision. Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
Gemfibrozil: May enhance the myopathic (rhabdomyolysis) effect of Simvastatin. Gemfibrozil may increase the serum concentration of Simvastatin. Concentrations of the active simvastatin acid metabolite may also be increased by gemfibrozil. Avoid combination
Glecaprevir and Pibrentasvir: May increase the serum concentration of Simvastatin. Avoid combination
Grapefruit Juice: May increase the serum concentration of Simvastatin. Avoid combination
Grazoprevir: May increase the serum concentration of Simvastatin. Monitor therapy
Green Tea: May increase the serum concentration of Simvastatin. Specifically, Simvastatin lactone concentrations may be increased. Monitor therapy
HMG-CoA Reductase Inhibitors (Statins): Niacin may enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy
Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
Imatinib: May decrease the metabolism of Simvastatin. Monitor therapy
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Lanthanum: HMG-CoA Reductase Inhibitors (Statins) may decrease the serum concentration of Lanthanum. Management: Administer HMG-CoA reductase inhibitors at least two hours before or after lanthanum. Consider therapy modification
Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Lercanidipine: May increase the serum concentration of Simvastatin. Management: Administer lercanidipine in the morning and simvastatin in the evening in patients receiving these drugs in combination. Consider therapy modification
Letermovir: May increase the serum concentration of Simvastatin. Avoid combination
Levamlodipine: May increase the serum concentration of Simvastatin. Management: Avoid the concurrent use of amlodipine with simvastatin when possible. If used together, avoid doses of simvastatin greater than 20 mg/day (for adults). Consider therapy modification
Lomitapide: May increase the serum concentration of Simvastatin. Management: Reduce the recommended simvastatin dose by 50%. Generally, limit the maximum adult simvastatin dose to 20 mg/day. A 40 mg/day dose can be considered in patients who previously received 80 mg/day for at least a year without evidence of muscle toxicity. Consider therapy modification
Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification
MiFEPRIStone: May increase the serum concentration of Simvastatin. Management: Avoid simvastatin during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination
Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification
Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Niacin: May enhance the myopathic (rhabdomyolysis) effect of Simvastatin. Niacin may increase the serum concentration of Simvastatin. Management: Use of simvastatin with niacin should be avoided in Chinese patients; some non-US labeling state this combination is not recommended in any Asian patients. Consider therapy modification
Niacinamide: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy
Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
PAZOPanib: Simvastatin may enhance the adverse/toxic effect of PAZOPanib. Specifically, the risk for ALT/AST elevations may be increased. Monitor therapy
Phenytoin: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Consider therapy modification
Protease Inhibitors: May increase the serum concentration of Simvastatin. Avoid combination
QuiNINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy
Raltegravir: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy
Ranolazine: May increase the serum concentration of Simvastatin. Management: Avoid the concurrent use of ranolazine with simvastatin when possible. If used together, avoid doses of simvastatin greater than 20 mg/day. Consider therapy modification
Red Yeast Rice: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Avoid combination
Repaglinide: HMG-CoA Reductase Inhibitors (Statins) may increase the serum concentration of Repaglinide. Monitor therapy
Rifamycin Derivatives: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Consider use of noninteracting antilipemic agents (note: pitavastatin concentrations may increase with rifamycin treatment). Monitor for altered HMG-CoA reductase inhibitor effects. Rifabutin and fluvastatin, or possibly pravastatin, may pose lower risk. Consider therapy modification
Rosuvastatin: Niacin may enhance the myopathic (rhabdomyolysis) effect of Rosuvastatin. Monitor therapy
Rupatadine: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Specifically, the risk for increased CPK and/or other muscle toxicities may be increased. Monitor therapy
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Simeprevir: May increase the serum concentration of Simvastatin. Monitor therapy
Simvastatin: Niacin may enhance the myopathic (rhabdomyolysis) effect of Simvastatin. Niacin may increase the serum concentration of Simvastatin. Management: Use of simvastatin with niacin should be avoided in Chinese patients; some non-US labeling state this combination is not recommended in any Asian patients. Consider therapy modification
St John's Wort: May increase the metabolism of HMG-CoA Reductase Inhibitors (Statins). Management: Consider avoiding the concomitant administration of St Johns Wort with interacting HMG-CoA reductase inhibitors in order to avoid the potential for decreased antilipemic effects. Monitor for decreased effects during concomitant therapy. Consider therapy modification
Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification
Telithromycin: May increase the serum concentration of Simvastatin. Avoid combination
Teriflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Monitor therapy
Ticagrelor: May increase the serum concentration of Simvastatin. Management: Avoid using doses of simvastatin greater than 40 mg/day with ticagrelor. This specific recommendation is found in the U.S. prescribing information but not in the Canadian product monograph. Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Tolvaptan: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Consider therapy modification
Trabectedin: HMG-CoA Reductase Inhibitors (Statins) may enhance the myopathic (rhabdomyolysis) effect of Trabectedin. Monitor therapy
Verapamil: May increase the serum concentration of Simvastatin. Management: Avoid concurrent use of verapamil with simvastatin when possible. If used together, limit adult maximum simvastatin dose to 10 mg/day, and avoid Simcor (simvastatin/niacin) because fixed simvastatin doses in the product exceed this maximum. Consider therapy modification
Vitamin K Antagonists (eg, warfarin): HMG-CoA Reductase Inhibitors (Statins) may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy
Voxilaprevir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Use the lowest statin dose possible if combined with voxilaprevir and monitor patients for increased statin effects/toxicities. Avoid concomitant use of voxilaprevir with rosuvastatin or pitavastatin, and limit pravastatin doses to 40 mg daily. Consider therapy modification
Test Interactions
Niacin: False elevations in some fluorometric determinations of plasma or urinary catecholamines; false-positive urine glucose (Benedict's reagent)
Adverse Reactions
Reactions/percentages reported with combination product; also see individual agents.
>10%: Cardiovascular: Flushing (≤59%)
1% to 10%:
Central nervous system: Headache (5%)
Dermatologic: Pruritus (3%)
Gastrointestinal: Diarrhea (3%), nausea (3%)
Neuromuscular & skeletal: Back pain (3%)
Frequency not defined:
Endocrine & metabolic: Abnormal thyroid function test, decreased serum phosphate, increased amylase, increased gamma-glutamyl transferase, increased lactate dehydrogenase, increased uric acid
Hematologic & oncologic: Increase in fasting plasma glucose, prolonged prothrombin time, thrombocytopenia
Hepatic: Increased serum alkaline phosphatase, increased serum bilirubin, increased serum transaminases
Neuromuscular & skeletal: Increased creatine phosphokinase
Warnings/Precautions
Concerns related to adverse effects:
- Flushing/pruritus: Flushing and pruritus are common adverse effects of niacin; may be attenuated with a gradual increase in dose, administering with food, avoidance of concurrent ingestion of ethanol or hot or spicy foods/liquids, and/or by taking aspirin 30 minutes before dosing. Flushing associated with extended-release preparation is significantly reduced (Guyton 2007). Consider discontinuation if persistent severe cutaneous symptoms occur during therapy.
- Gastrointestinal effects: May cause gastrointestinal distress, vomiting, diarrhea, or aggravate peptic ulcer; gastrointestinal distress may be attenuated with a gradual increase in dose and administration with food. Use is contraindicated in patients with active peptic ulcer disease; use with caution in patients with a past history of peptic ulcer. Consider discontinuation if unexplained abdominal pain/weight loss or other gastrointestinal symptoms occur during therapy.
- Hematologic effects: Dose-related reductions in platelet count and increases of prothrombin time may occur.
- Hepatotoxicity: Cases of severe hepatotoxicity, including fulminant hepatic necrosis, have occurred when immediate release (crystalline) niacin products have been substituted with sustained-release (modified release, timed-release) niacin products at equivalent doses. Patients should be initiated with low doses with titration to achieve desired response. Persistent elevations in serum transaminases have been reported with simvastatin; upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels. Postmarketing reports of fatal and nonfatal hepatic failure with simvastatin have been reported and are rare. If serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, interrupt therapy promptly; if an alternate etiology is not identified, do not restart. Liver enzyme tests should be obtained at baseline and as clinically indicated. Discontinue use if hepatic transaminase levels rise, particularly to 3 x ULN and are persistent, or if they are associated with symptoms of nausea, fever, and/or malaise.
- Hypophosphatemia: Niacin has been associated with small but statistically significant dose-related reductions in phosphorus levels. Monitor phosphorus levels periodically in patients at risk for hypophosphatemia.
- Myopathy/rhabdomyolysis: Rhabdomyolysis with or without acute renal failure secondary to myoglobinuria and/or myopathy has been reported; patients should be monitored closely. This risk is dose-related and is increased with high doses of simvastatin (80 mg) or niacin (doses ≥1 g/day). Concomitant use of strong CYP3A4 inhibitors (eg, clarithromycin, erythromycin, itraconazole, ketoconazole, nefazodone, posaconazole, voriconazole, protease inhibitors [including boceprevir and telaprevir], telithromycin, cobicistat-containing products), cyclosporine, danazol, and gemfibrozil is contraindicated due to increased risk of myopathy. Use with caution in patients with uncontrolled hypothyroidism, patients taking other drugs associated with myopathy (eg, colchicine), ≥ 65 years of age, and women; these patients are predisposed to myopathy. Immune-mediated necrotizing myopathy (IMNM) associated with HMG-CoA reductase inhibitors use has also been reported. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine, particularly if accompanied by malaise or fever. Discontinue therapy if markedly elevated CPK levels occur or myopathy is diagnosed/suspected.
Disease-related concerns:
- Cardiovascular disease: Use with caution in patients with unstable angina or MI. In patients with pre-existing coronary artery disease, the incidence of atrial fibrillation was observed more frequently in those receiving immediate release (crystalline) niacin as compared to placebo (Coronary Drug Project Research Group 1975). Consider discontinuation if new-onset atrial fibrillation occurs during therapy.
- Diabetes: Niacin is associated with new-onset diabetes or worsening glucose tolerance in patients with preexisting diabetes (Garg 2017; Goldie 2016); use with caution in patients with diabetes. Monitor glucose; adjustment of diet and/or hypoglycemic therapy may be necessary. Consider discontinuation if persistent hyperglycemia occurs during therapy.
- Gout: Niacin may be associated with hyperuricemia; use with caution in patients with gout. Consider discontinuation if acute gout occurs during therapy.
- Hepatic impairment: Use with caution in patients with a past history of hepatic impairment; monitor liver function tests. Contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases.
- Renal impairment: Use with caution in renal impairment; use with extreme caution or avoid in severe impairment unless patient already tolerating simvastatin doses ≥10 mg. Renal impairment may also increase risk for myopathy.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Special populations:
- Chinese patients: Increased risk for myopathy in Chinese patients with simvastatin; use with caution. Do not use high dose simvastatin (80 mg) if concurrently taking niacin ≥1 g/day.
- Elderly: Use with caution in patients ≥65 years of age; these patients are predisposed to myopathy.
- Surgical patients: The manufacturer recommends temporary discontinuation for elective major surgery, acute medical or surgical conditions, or in any patient experiencing an acute or serious condition predisposing to renal failure (eg, sepsis, hypotension, trauma, uncontrolled seizures). Based on current research and clinical guidelines, HMG-CoA reductase inhibitors should be continued in the perioperative period. Postoperative discontinuation of statin therapy is associated with an increased risk of cardiac morbidity and mortality (ACC/AHA [Fleisher 2014]).
Dosage form specific issues:
- Product interchangeability: Bioavailability of niacin formulations vary (regular release versus extended release) and are not interchangeable; cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted niacin products at equivalent doses.
Other warnings/precautions:
- Alcohol use: Use with caution in patients who consume large amounts of ethanol due to the increased risk of liver dysfunction.
Monitoring Parameters
2013 ACC/AHA Blood Cholesterol Guideline recommendations (Stone 2013):
Lipid panel (total cholesterol, HDL, LDL, triglycerides): Baseline lipid panel; fasting lipid profile within 4 to 12 weeks after initiation or dose adjustment and every 3 to 12 months (as clinically indicated) thereafter. If 2 consecutive LDL levels are <40 mg/dL, consider decreasing the dose.
Hepatic transaminase levels: Baseline measurement of hepatic transaminase levels (ie, ALT); measure hepatic function if symptoms suggest hepatotoxicity (eg, unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine or yellowing of skin or sclera) during therapy.
CPK: CPK should not be routinely measured. Baseline CPK measurement is reasonable for some individuals (eg, family history of statin intolerance or muscle disease, clinical presentation, concomitant drug therapy that may increase risk of myopathy). May measure CPK in any patient with symptoms suggestive of myopathy (pain, tenderness, stiffness, cramping, weakness, or generalized fatigue).
Evaluate for new-onset diabetes mellitus during therapy; if diabetes develops, continue statin therapy and encourage adherence to a heart-healthy diet, physical activity, a healthy body weight, and tobacco cessation.
If patient develops a confusional state or memory impairment, may evaluate patient for nonstatin causes (eg, exposure to other drugs), systemic and neuropsychiatric causes, and the possibility of adverse effects associated with statin therapy.
Baseline fasting blood glucose or hemoglobin A1c and uric acid before initiation and repeat during uptitration to maintenance dose and every 6 months thereafter.
Manufacturer's labeling: Platelets/prothrombin time (if on anticoagulants); phosphorus (if predisposed to hypophosphatemia)
Pregnancy
Pregnancy Risk Factor
X
Pregnancy Considerations
Use is contraindicated in women who are or who may become pregnant. See individual monographs for additional information.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?
- Patient may experience flushing or headache. Have patient report immediately to prescriber prescriber signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes),, severe dizziness, passing out, chest pain, fast heartbeat, shortness of breath, sweating a lot, unable to pass urine, change in amount of urine passed, severe muscle pain, or severe muscle weakness (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.
